Recovery Act Limited Competition: NIH Challenge Grants in Health and Science Research (RC1) RFA-OD-09-003 Broad Challenge Area: 15, Translational Science Research Area: 15-MH-109 Prefrontal cortex regulation of higher brain function and complex behaviors. Summary/Abstract The prefrontal cortex (PFC) plays an important role in executive function, including the control of attention. Lesions of PFC impair the ability to focus attention, ignore distracters, and switch attention in a flexible manner. The cognitive dysfunctions found in schizophrenia and other mental disorders likely involve some dysfunction of the PFC, and thus, understanding the functional circuitry that mediates cognitive function in PFC is consistent with the NIMH strategic plan. In spite of all the evidence that top-down feedback from PFC to the sensory association cortex is important for the control of attention and other cognitive functions, the nature of the PFC feedback is still unclear. We recently found that one key component of this mechanism may be phase-coupled gamma-frequency synchrony between PFC and the association cortex. Synchrony between the frontal eye field (FEF, within PFC) and area V4 (within association cortex) is strongly modulated by attention. Most importantly, the cross area synchrony is shifted in time by 8-12 ms, which appears to be just the right amount of time to allow for conduction and synaptic delays between the two areas. Thus, spikes from one area will begin to affect cells in the coupled area when they are maximally depolarized and prepared to receive new input. Such phase- coupled synchrony during attention may generally allow PFC to communicate effectively with other cortical areas. However, neurophysiological data such as these necessarily reveal only correlations between neural activity and behavior, not causality. The proposed studies will directly test whether the phase coupled oscillations between FEF and V4 cause firing rate changes and mimic the effects of attention on behavior. For these tests, we will use novel new optogenetic technology, which we have recently demonstrated can be used for stimulating primate neurons with millisecond precision. Using optogenetic tools, we will simultaneously stimulate FEF and record from area V4. We will stimulate FEF cells at gamma frequencies (~ 40 Hz), and we will dynamically adjust the phase of stimulation to maintain a time/phase delay of approximately 8-12 ms relative to the phase of local field potentials in V4. Stimulation with this time delay should maximize the response of V4 cells to a stimulus in the RF, thereby mimicking the effects of attention on V4 responses and the animal's behavior. Conversely, we will stimulate in V4 and test the effects of stimulation phase on the ability of bottom-up signals from V4 to drive cells in FEF. Positive evidence that phase-coupled synchrony between PFC and other cortical areas plays an important role in the regulation of attention would have a major impact on our understanding of PFC's role in cognition. More specifically, a dysfunction of neural synchrony in PFC may contribute to the cognitive dysfunctions in schizophrenia, and positive results from the present application would potentially provide an important lead in understanding the role of impaired cross-area communication. . PUBLIC HEALTH RELEVANCE: The proposed research seeks to understand the fundamental biological mechanisms of attention in prefrontal cortex. This research addresses a critical public health need, as disorders of attention are common in many mental disorders, including schizophrenia, depression, and ADHD. These disorders affect millions of Americans and current treatments remain inadequate for many people.